The present invention relates to polymeric compounds and methods of formulating same, said polymeric compounds having a polyacrolein sub-unit in aldehyde, hydrated, hemi-acetal or acetal form and having biostatic or biocidal properties. More particularly, the present invention is directed to compositions containing the above noted polymeric compounds and the biostatic and/or biocidal uses of these compositions.
The broad-based antimicrobial properties of polymers having the repeating polymeric unit: 
or this unit in its hydrated, hemi-acetal or acetal form, represented by the formulae: 
wherein R is hydrogen or alkyl and n is an integer of one or more have been demonstrated previously (International Patent Application Publication WO 88/04671). The compounds particularly described therein include poly(2-propenal, 2-propenoic acid).
It has also been noted previously (International Patent Application Publication WO 96/38186) that poly(2-propenal, 2-propenoic acid) is formed when the aldehyde groups of poly (2-propenal) syn polyacrolein are partially auto-oxidised to carboxyl groups. It was further noted that the polymer is soluble in dilute aqueous bases, for example aqueous sodium carbonate.
It is known that antimicrobial compositions may be used as preservatives, or as the active ingredients in disinfectants, dermatological compositions including sun screen formulations or antiseptic formulations, or in animal feed additives.
Generally these antimicrobial compositions must:
be stable;
be efficacious in killing micro-organisms within a specified time;
be safe, that is be reasonably free of toxicity which may be caused by the trans-dermal migration of low molecular weight ingredients into the blood-stream so as to manifest toxicity, antigenicity, allergy, irritation or inflammation;
have minimal odour; and
in some dermatological preparations, have the property of sun screening and minimise adverse dermatological sffects from the generation of free-radicals.
Specifically, antimicrobial formulations applied to inanimate objects and the skin are usually termed disinfectants and antiseptics, respectively. Often, regulatory standards demand that a disinfectant formulation first, is stable and secondly, kills a chosen quantum of vegetative micro-organisms within 10 minutes. That is, the antimicrobial activity of these compositions must be biocidal and quick. The formulations described herein are substantially aimed at these goals, but often achieve more, for example killing even extremely resistant bacterial spores within the frequent standard of 24 hours.
Formulation of poly(2-propenal, 2-propenoic acid) simply by dissolution in dilute aqueous sodium carbonate, and then neutralisation to pH 7, has now been found to provide a composition that does not always kill micro-organisms fast enough to meet the above standards.
It is one object of the present invention to provide methods of preparing compositions containing compounds of the type described by the prior art and in particular poly(2-propenal, 2-propenoic acid), and which are useful disinfectants and/or antiseptics meeting these standards.
It is a further object of the present invention to provide a method of preparing polymers and/or copolymers derived from acrolein in accordance with the above mentioned prior art for use as useful disinfectants and/or antiseptics.
It is a still further object of the present invention to provide a method of preparing polymers and/or copolymers derived from acrolein in accordance with the above mentioned prior art, for use in dermatological formulations, including sunscreens.
It is yet still a further object of the present invention to provide a method of preparing polymers and/or copolymers derived from acrolein in accordance with the above mentioned prior art for use in other applications including as a preservative or as an animal feed-additive.
Throughout this specification, unless the context requires otherwise, the word xe2x80x9ccomprisexe2x80x9d, or variations such as xe2x80x9ccomprisesxe2x80x9d or xe2x80x9ccomprisingxe2x80x9d, will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.
In accordance with the present invention there is provided a method for the preparation of compositions of poly(2-propenal, 2-propenoic acid) comprising the method steps of dissolving the poly(2-propenal, 2-propenoic acid) in aqueous base, adding an organic compound containing one or more hydrophobic groups, and subsequently acidifying the solution, whereby interaction between the hydrophobic groups of the organic compound and the poly(2-propenal, 2-propenoic acid) prevents precipitation of the poly(2-propenal, 2-propenoic acid) occurring at pH xe2x89xa75.5 and the solution is consequently stable over a broad pH range.
Preferably, the precipitation of the poly(2-propenal, 2-propenoic acid) is prevented at pH xe2x89xa73.5.
The organic compound may be an anionic surfactant. The anionic surfactant is preferably selected from either sodium lauryl sulphate or disodium decyl (sulfophoxy) benzene sulfonate and disodium oxybis (decylsulfophenoxy) benzene sulfonate.
In one form of the invention, one or more phenols may be added to the solution of poly(2-propenal, 2-propenoic acid) prior to acidification. The phenol is preferably o-phenyl-phenol.
In a further form of the invention, the composition containing poly(2-propenal, 2-propenoic acid) is firstly stored for a time in basic composition prior to addition of surfactant and acidification.
In a still further form of the invention, the composition exhibits increased antimicrobial activity, the method of preparing the composition comprising preparation of the poly(2-propenal, 2-propenoic acid) in the presence of air and/or oxygen, with or without inhibitor. Alternately, the method comprises the subsequent making of the composition of poly(2-propenal, 2-propenoic acid) into a basic composition.
Preferably, the organic compound is one or more of ethylene diamine tetra acetic acid, a lower alkanol, a phenol, isothiazolinones and glutaraldehyde, the composition exhibiting a synergistic increase in antimicrobial activity.
The composition may further comprise phenols and/or glutaraldehyde, whereby the odour of the phenols and/or glutaraldehyde is reduced by the presence of the poly(2-propenal, 2-propenoic acid).
The composition may exhibit reduced trans-dermal migration of low molecular weight components of the composition as a result of the presence of poly(2-propenal, 2-propenoic acid). The low molecular weight composition may contain a sunscreen agent. The sunscreen agent may be either or both of octyl methoxy cinnamate and octyl dimethyl p-aminobenzoate.
In one form of the invention, the composition, especially for dermatological use, exhibits a sunscreening effect as a result of the presence of poly(2-propenal, 2-propenoic acid).
In another form of the invention, the composition exhibits the formation of a continuous antimicrobial film on substrates.
In another form of the invention, the composition, especially for dermatological use exhibits a free-radical scavenging effect as the result of the presence of poly(2-propenal, 2-propenoic acid).
In accordance with the present invention there is provided an aqueous polymeric composition comprising poly(2-propenal, 2-propenoic acid) and an organic compound containing one or more hydrophobic groups, wherein interaction between the hydrophobic groups of the organic compound and the poly(2-propenal, 2-propenoic acid) prevents the precipitation of the poly(2-propenal, 2-propenoic acid) at pH  greater than 5.5.
Preferably, the poly(2-propenal, 2-proppnoic acid) does not precipitate at a pH 2 3.5.
Still preferably, the organic compound is an anionic surfactant. The anionic surfactant may be chosen from either sodium lauryl sulphate or disodium decyl (sulfophoxy) benzene sulfonate and disodium oxybis (decylsulfophenoxy) benzene sulfonate.
The composition may further comprising one or more phenol. The phenol may be o-phenyl-phenol.
In one form of the invention, the composition further comprises one or more of ethylene diamine tetra acetic acid, a lower alkanol, a phenol, isothiazolinones and glutaraldehyde, the composition exhibiting a synergistic increase in antimicrobial activity.
The composition may be an emulsion.
In accordance with the present invention there is still further provided the use of the above defined compositions for antimicrobial uses, for dermatological uses, or for use as a feed additive.
It has now been discovered that modifying the preparation of poly(2-propenal, 2-propenoic acid) as described in both WO 88/04671 and WO 96/38186 (Example 1b in each) by concurrently bubbling in air and/or oxygen during the polymerisation, produces a polymer with more discreet crystalline form which aids recovery and subsequent drying, and in solid or in liquid medium has less contaminating and slightly odorous oligomers, and has higher inherent rate of antimicrobial activity; see Example 1 hereinafter.
It has now been found that whilst basic aqueous compositions containing the poly(2-propenal, 2-propenoic acid) are biostatic and/or biocidal; nevertheless, the compostions are appreciably unstable. Although, it has further been shown that lowering the pH (lowering the hydroxyl ion concentration) of such compositions/solutions increases their chemical stability, counter-productively, it has been found that acidification of the composition to pH""s below approximately pH 6, causes precipitation of the poly(2-propenal, 2-propenoic acid).
It has now been shown that this precipitation can be avoided until approximately pH 3.5 (ie. over ten-fold, less hydroxyl ion concentration), by a method of formulating in which the poly(2-propenal, 2-propenoic acid) is first dissolved in dilute aqueous base, then anionic surfactant added, before the acidification. Useful anionic surfactants are either sodium lauryl sulphate (xe2x80x9cSLSxe2x80x9d) or disodium decyl (sulfophoxy) benzene sulfonate and disodium oxybis (decylsulfophenoxy) benzene sulfonate in equal weight ratios with the poly(2-propenal, 2-propenoic acid). To be effective, it is important to maintain this order of addition, so that the poly(2-propenal, 2-propenoic acid) is in its anionic form before the addition of the surfactant; see Example 2 hereinafter. This apparent interrelationship between the two negatively charged species from poly(2-propenal, 2-propenoic acid), and anionic detergent is surprising since repulsion between the like-charges on the species would be expected.
It has now been found that basic aqueous solutions of poly(2-propenal, 2-propenoic acid) kill micro-organisms more rapidly than do acidic solutions of the polymer. This discovery led to the further finding that formulations of more stable, acidic compositions containing poly(2-propenal, 2-propenoic acid) and preferably, anionic surfactant, could subsequently be made basic and hence, more antimicrobially active, immediately before use as, for example, either a disinfectant and/or antiseptic and/or preservative; see Example 10 hereinafter.
It has now been shown that if a solution of poly(2-propenal, 2-propenoic acid) which contains a phenol, with anionic surfactant is acidified, a surprisingly stable emulsion is formed, and in this heterogenous system, the poly(2-propenal, 2-propenoic acid) in the hydrophobic phase is protected from chemical degradation by the hydroxyl ions in the hydrophilic phase; see Example 2 hereinafter. o-Phenyl-phenol is particularly useful, and in equal weight ratio with the poly(2-propenal, 2-propenoic acid).
It has now been shown that the inclusion of phenols additionally to anionic surfactants in compositions containing poly(2-propenal, 2-propenoic acid) allows further acidification of these compositions before any precipitation of the poly(2-propenal, 2-propenoic acid) ie. further chemical stability with respect to hydroxyl ion and/or base is achieved; see Example 2 hereinafter. Further, it has now been shown that if the composition containing poly(2-propenal, 2-propenoic acid) only is firstly stood, for example for about 11 days at about pH 9, in an aqueous alkaline medium, before the addition of the anionic surfactant and then phenol-precipitation will not occur at all, upon acidification; see Example 2 hereinafter.
It has now been shown that co-formulation of the composition containing poly(2-propenal, 2-propenoic acid), with anionic surfactant, and optionally with additionally a phenol, produces a composition which provides a continuous antimicrobial film upon substrates, after application thereto, eg. skin, flooring, walls furniture etc. Without these additives, the film is invariably discontinuous and hence only partially protects the substrate, antimicrobially. It has now been shown that these films retain moisture, facilitating their protective antimicrobial activities. If they also contain a volatile component which effects their pH-dependent antimicrobial activities, then, in turn, these activities may be increased as evaporation takes place; see Example 10 hereinafter.
It has now been shown that inclusion of anionic surfactant in formulations containing poly(2-propenal, 2-propenoic acid), increases their chemical stability to hydroxyl ion and/or base; see Example 3 hereinafter.
It has now been shown that poly(2-propenal, 2-propenoic acid) absorbs in the UV, and that a peak about 268 nm, as it is replaced by absorption at approximately 232 nm, correlates with and is a convenient monitor of the chemical stability of poly(2-propenal, 2-propenoic acid) in basic aqueous solutions; see xe2x80x9cStability Testxe2x80x9d hereinafter.
It has now been shown that co-formulating anionic surfactant and/or ethylenediaminetetraacetic (xe2x80x9cEDTAxe2x80x9d) acid and/or its salts and/or a lower alkanol enhances the antimicrobial properties of compositions containing the poly(2-propenal, 2-propenoic acid); see Examples 4 and 5 hereinafter.
It has now been shown, further, that not only is the antimicrobial activity increasedxe2x80x94but surprisingly, it is synergistically increased by incorporating in the compositions containing the poly(2-propenal, 2-propenoic acid) either, EDTA (and/or its salts), and/or phenols, and/or isothiazolinones, and/or glutaraldehyde; see Example 7 hereinafter.
It has now been shown that inclusion of poly(2-propenal, 2-propenoic acid) decreases the notorious odours of compositions containing antimicrobial phenol(s) and/or glutaraldehyde; see Example 6 hereinafter.
It has now been shown that the surprising apparent interaction between the negatively-charged phenols and the negatively-charged anionic form of poly(2-propenal, 2-propenoic acid) is more general, and is thought to result from the interaction of the hydrophobic portions of the respective species. Thus, the presence of poly(2-propenal, 2-propenoic acid) in an emulsion with the UV sunscreen octyl methoxy cinnamate, or octyl dimethyl p-aminobenzoate, is shown to prevent the migration of either of the sunscreens through a membrane which is a model for the skin; see Example 8 hereinafter. Hence, it is apparent that poly(2-propenal, 2-propenoic acid) may be used as a co-formulant to reduce potential toxicity and/or allergy and/or antigenicity and/or irritation and/or inflammation from sunscreen agents, or other compounds, eg. phenols, which results from trans-dermal migration of such constituents, in dermatological preparations, into the blood-stream.
It has been shown further, that the peak at 268 nm and below provides significant UVC absorption. UVC energy is greater than 50% of the energy in sunlight (Lide, D. R., xe2x80x9cCRC Handbook of Chemistry and Physicsxe2x80x9d, CRC Press, 73rd edition, 1992-93, page 14-8) and is in the wavelength to which the skin is most sensitive (xe2x80x9cHarry""s Cosmeticologyxe2x80x9d, J. B. Wilkinson and R. J. Moore Eds., Chemical Publishing Co. Inc., New York, 1982, page 228) and which induces changes that alter the structure of DNA (Kano R. J. and Colome J. S. xe2x80x9cMicrobiologyxe2x80x9d, West Publishing Company, 1986, page 162). Thus, it has now been found that it is an advantage to include poly(2-propenal, 2-propenoic acid) in dermatological sunscreen preparations.
It has now been shown that compositions containing poly(2-propenal, 2-propenoic acid) and containing only polymeric ingredients (eg. polymeric solvents/emollients and/or polymeric surfactants and/or emulsifiers) and/or volatile ingredients provide compositions for dermatological applications, free of any components which, after spreading on the skin, may migrate trans-dermally and into the bloodstream to cause toxicity, allergy etc; see Example 8 hereinafter.
It has now been shown that the formulation of such compositions (eg free of conventional surfactants) is facilitated by the surfactant properties of poly(2-propenal, 2-propenoic acid).
It has now been shown that poly(2-propenal, 2-propenoic acid) has the capacity to absorb free-radicals and this is a distinct use in dermatological compositions with a view to minimising skin-damage brought about by free-radicals; see Example 9 hereinafter.
It has now been shown that the methods, compnositions and uses provided herein, apply to all compounds described in WO 88104671 and WO 96138186, particularly those compounds which are hydrophilic and/or soluble in aqueous media; the methods shown herein of keeping these compounds in solution and/or emulsion in aqueous media generally facilitate any desired chemical reactions with these compounds in acidic media.